On December 1, 2018 The Janssen Pharmaceutical Companies of Johnson & Johnson reported long-term results from the Phase 3 ALCYONE study showing that the addition of Darzalex (daratumumab) to bortezomib, melphalan and prednisone (VMP) continued to demonstrate significant improvement in progression-free survival (PFS) in patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation (ASCT) (Press release, Johnson & Johnson, DEC 1, 2018, View Source [SID1234531790]).1 These data (Abstract #156), as well as updates from the Phase 2 LYRA (Abstract #152) and GRIFFIN (Abstract #151) studies in patients with multiple myeloma, were featured during an oral abstract session at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, CA.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Long-term Phase 3 ALCYONE results for daratumumab frontline combination therapy1

At a median follow-up of 27.8 months, study results showed the addition of daratumumab to VMP reduced the risk of disease progression or death by 57 percent compared to VMP alone (Hazard Ratio [HR] = 0.43; 95 percent confidence interval [CI] 0.35-0.54, p<0.0001).1 Daratumumab-VMP resulted in a 24 month PFS rate of 63 percent compared to 36 percent with VMP alone.1 The median PFS for daratumumab-VMP has not yet been reached, whereas the control arm of VMP alone had a median PFS of 19.1 months.1 In addition, a significantly higher overall response rate (ORR) (91 percent vs. 74 percent, respectively) was observed with the daratumumab combination compared to VMP alone.1 Daratumumab-VMP resulted in deeper responses, significantly improving the rate of very good partial response (VGPR) or better (73 percent vs. 50 percent) and more than doubling the rate of stringent complete response (sCR) (22 percent vs. 8 percent) compared to VMP alone.1 Daratumumab-VMP induced a higher rate of sustained minimal residual disease (MRD) negativity compared to VMP alone (10 percent vs. 2 percent, respectively).1 The previously reported primary results of this study formed the basis of the European Commission approval of daratumumab in combination with VMP in patients with newly diagnosed multiple myeloma who are ineligible for ASCT.

"Longer-term data from the pivotal ALCYONE trial show that daratumumab combination therapy continued to show improvement in progression-free survival and response rates in newly diagnosed patients with multiple myeloma, including older patients who are less likely to respond to treatment," said Meletios A. Dimopoulos, M.D., Professor and Chairman of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine, Athens, Greece, and principal investigator. "These promising results support the use of daratumumab earlier in the treatment paradigm when transplant ineligible patients are more likely to benefit from therapy, and that continued therapy with daratumumab confers benefit."

In the ALCYONE study, the most common Grade 3/4 treatment-emergent adverse events (TEAEs) during Cycle 10 and onward for daratumumab-VMP included anaemia (4 percent), neutropenia (2 percent) and bronchitis (1 percent).1 No new safety signals emerged, and Grade 3/4 infections continued to be manageable.1

Phase 2 LYRA and GRIFFIN data support efficacy and safety of daratumumab in newly diagnosed patients, including those who are eligible for high-dose therapy/ASCT, and in relapsed patients2,3

Response rates from the Phase 2 LYRA study were presented for the investigational use of daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in patients with newly diagnosed and relapsed multiple myeloma.2 The ORR and VGPR or better rates in 86 newly diagnosed patients were 79 percent and 44 percent, respectively, after 4 Cycles and increased to 81 percent and 56 percent, respectively, at the end of induction (median 6 Cycles).2 In addition, the VGPR or better rate in 14 relapsed multiple myeloma patients was 57 percent after 4 Cycles and increased to 64 percent at the end of induction, and the ORR stayed consistent at 71 percent (median 7.5 Cycles).2 The 18-month PFS rate was 78 percent in non-transplant newly diagnosed patients and 53 percent in relapsed patients.2 Additionally, the study, which investigated splitting the first dose of daratumumab to shorten the infusion time on Cycle 1, Day 1 (C1D1), showed a safety profile consistent with previous studies.2 Infusion reactions (IRs) occurred in 49 percent of patients on C1D1 and four percent on Cycle 1, Day 2 (C1D2). Fifty-four percent of newly diagnosed patients experienced IRs, the most frequent being chills (14 percent), dyspnea, pruritus and nausea (8 percent each), and cough (7 percent). Fifty-seven percent of relapsed patients experienced IRs, the most frequent being cough (21 percent), hyperhidrosis, dyspnea, and chills (7 percent each). Only two patients experienced a Grade 3 IR, and there were no Grade 4 IRs. There were no daratumumab discontinuations due to IRs. Median infusion time was 4.5 hours for C1D1 and 3.8 hours for C1D2.2 Grade 3/4 TEAEs were reported for 56 percent of patients and the most common (≥10 percent) was neutropenia (13 percent).2

Data presented on the Phase 2 GRIFFIN study investigated daratumumab in combination with bortezomib, lenalidomide and dexamethasone (VRd) in a 16-patient safety cohort of newly diagnosed patients with multiple myeloma who were eligible for high-dose therapy and ASCT.3 Results showed that by the end of consolidation therapy following ASCT, all patients enrolled in the safety run-in obtained VGPR or better, and 63 percent achieved complete response (CR) or better, including 25 percent of patients who achieved sCR.3 Additionally, 94 percent of patients remained progression-free on study treatment at a median follow-up of 16.8 months.3 In addition, 8 of the 16 patients (50 percent) were MRD negative at a level of 10-5 by the end of consolidation.3 Fourteen patients (88 percent) experienced Grade 3/4 TEAEs with 10 (63 percent) related to treatment with daratumumab.3 The most common Grade 3/4 TEAEs (≥10 percent) included neutropenia, pneumonia, thrombocytopaenia, lymphopenia, febrile neutropenia, leukopenia, rash and hypophosphataemia.3 Thirteen patients (81 percent) experienced infections of any grade, including upper respiratory tract infection (six patients), pneumonia (four patients), bronchitis (two patients), and otitis and viral gastroenteritis (two patients each).3 No deaths due to serious adverse events were reported and no patient discontinued treatment due to an adverse event.3 These data suggest that daratumumab induction does not negatively impact stem cell mobilisation as all 16 patients underwent successful mobilisation with subsequent ASCT.3

"Daratumumab offers consistent clinical benefit across all lines of therapy in multiple myeloma and the positive data from the ALCYONE, LYRA and GRIFFIN studies build on the strong body of evidence supporting daratumumab-based regimens," said Dr Catherine Taylor, Haematology Therapy Area Lead, Europe, Middle East and Africa (EMEA), Janssen-Cilag Limited. "These are important findings for patients which also provide additional insight into the most effective ways to manage care."

#ENDS#

About the ALCYONE Trial4

The randomised, open-label, multicentre Phase 3 ALCYONE (MMY3007) study enrolled 706 newly diagnosed patients with multiple myeloma who were ineligible for high-dose chemotherapy with ASCT. The median age was 71 years (range: 40-93). Patients were randomised to receive up to nine Cycles of either daratumumab-VMP or VMP alone. In the daratumumab-VMP arm, patients received 16 mg/kg of daratumumab once weekly for the first week (Cycle 1), followed by once every three weeks (Cycles 2-9). Following the nine cycles, patients in the daratumumab-VMP arm continued to receive 16 mg/kg of daratumumab once every four weeks until disease progression.

About the LYRA Trial5

The ongoing, multicentre, single-arm, open-label Phase 2 LYRA (MMY2012) study enrolled 100 adult patients 18 years or older. Patients received 4-8 Cycles of daratumumab combination therapy comprised of oral cyclophosphamide 300 mg/m2 on Days 1, 8, 15 and 22; subcutaneous bortezomib 1.5 mg/m2 on Days 1, 8 and 15; and oral or IV dexamethasone 40 mg weekly every 28 days. Daratumumab was administered at 8 mg/kg IV on Days 1 and 2 of Cycle 1, 16 mg/kg weekly from Cycle 1, Day 8 through Cycle 2, 16 mg/kg every 2 weeks for Cycles 3-6, and 16 mg/kg every 4 weeks for Cycles 7-8. After induction, patients could undergo ASCT. All patients receive 12 cycles of maintenance daratumumab 16 mg/kg IV every 4 weeks.

About the GRIFFIN Trial6

The randomised, open-label Phase 2 GRIFFIN (MMY2004) study has enrolled and treated more than 200 adults 18-70 years eligible for high-dose therapy/ASCT,7 including 16 patients in a safety run-in phase performed to assess potential dose limiting toxicities during Cycle 1 of daratumumab combination with VRd. Patients in the safety run-in received four infusion Cycles of daratumumab and VRd every 21 days followed by stem cell mobilisation, high-dose therapy and ASCT; two consolidation Cycles of daratumumab and VRd; and maintenance therapy with daratumumab and lenalidomide for Cycles 7-32. During induction and consolidation (Cycles 1-6), patients received 25 mg of lenalidomide orally on Days 1-14, 1.3 mg/m2 of bortezomib subcutaneously on Days 1, 4, 8 and 11, and 20 mg of dexamethasone on Days 1, 2, 8, 9, 15 and 16 every 21 days. Daratumumab 16 mg/kg IV was given on Days 1, 8 and 15 of Cycles 1-4 and on Day 1 of Cycles 5-6. During maintenance (Cycles 7-32), patients receive 10 mg daily of lenalidomide (15 mg beginning at Cycle 10 if tolerated) on Days 1-21 every 28 days and daratumumab 16 mg/kg IV every 56 days; this was amended to every 28 days. Maintenance therapy with lenalidomide may be continued beyond Cycle 32 per local standard of care. In the subsequent randomised Phase 2 portion of the study, approximately 200 patients were randomised and received treatment with VRd, ASCT and maintenance therapy with lenalidomide or daratumumab and VRd, ASCT and maintenance therapy with daratumumab and lenalidomide.7

About daratumumab

Daratumumab is a first-in-class biologic targeting CD38, a surface protein that is highly expressed across multiple myeloma cells, regardless of disease stage.8 Daratumumab is believed to induce tumour cell death through multiple immune-mediated mechanisms of action, including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), as well as through apoptosis, in which a series of molecular steps in a cell lead to its death.9 A subset of myeloid derived suppressor cells (CD38+ MDSCs), CD38+ regulatory T cells (Tregs) and CD38+ B cells (Bregs) were decreased by daratumumab.9 Daratumumab is being evaluated in a comprehensive clinical development programme across a range of treatment settings in multiple myeloma, such as in frontline and relapsed settings.10,11,12,13,14,15,16,17 Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant haematologic diseases in which CD38 is expressed, such as smouldering myeloma.18,19 For more information, please see www.clinicaltrials.gov.

In Europe, daratumumab is indicated for use in combination with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant, as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy, and in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.9 For further information on daratumumab, please see the Summary of Product Characteristics at View Source

In August 2012, Janssen Biotech, Inc. and Genmab A/S entered a worldwide agreement, which granted Janssen an exclusive licence to develop, manufacture and commercialise daratumumab.20

About Multiple Myeloma

Multiple myeloma (MM) is an incurable blood cancer that starts in the bone marrow and is characterised by an excessive proliferation of plasma cells.21 More than 45,000 people were diagnosed with multiple myeloma in Europe in 2016, and more than 29,000 patients died.22 Up to half of newly diagnosed patients do not reach five-year survival,23 and almost 29% of patients with multiple myeloma will die within one year of diagnosis.24

Although treatment may result in remission, unfortunately, patients will most likely relapse as there is currently no cure.25 Refractory multiple myeloma is when a patient’s disease progresses within 60 days of their last therapy.26,27 Relapsed cancer is when the disease has returned after a period of initial, partial or complete remission.28 While some patients with MM have no symptoms at all, most patients are diagnosed due to symptoms that can include bone problems, low blood counts, calcium elevation, kidney problems or infections.29 Patients who relapse after treatment with standard therapies, including PIs and immunomodulatory agents, have poor prognoses and few treatment options available.30

On December 1, 2018 Oxford BioMedica plc ("Oxford BioMedica" or "the Group") (LSE:OXB), a leading gene and cell therapy group, reported by Novartis on the longer-term analyses of both the ELIANA and JULIET pivotal trials in children and young adult patients with relapsed or refractory (r/r) acute lymphoblastic leukaemia (ALL) and adult patients with r/r diffuse large B-cell lymphoma (DLBCL), respectively. Kymriah (tisagenlecleucel) continued to demonstrate strong efficacy with durable responses and maintained a consistent and well-characterised safety profile (Press release, Oxford BioMedica, DEC 1, 2018, View Source [SID1234531789]). These data are being presented at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting. Additionally, today, the New England Journal of Medicine published online the 14-month results from JULIET, the study led by the Abramson Cancer Center at the University of Pennsylvania 1.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

In the 24-month follow-up analysis of the ELIANA study in children and young adults with r/r B-cell ALL, Kymriah demonstrated deep and durable responses without subsequent therapy in a significant portion of patients in this population. Among 79 evaluable patients, who were followed for at least three months or discontinued earlier, 82% (95% confidence interval [CI], 72% – 90%) achieved complete response (CR) or CR with incomplete blood count recovery (CRi) within three months of infusion; and among these responding patients, 98% had negative minimal residual disease (MRD). The relapse-free survival rate was 62% at 24 months; and the median duration of remission (mDOR) and median overall survival (mOS) remained unreached, signifying responses are deep and sustained, and further reinforcing the potential for Kymriah to be a definitive therapy for many patients. The probability of OS was 76% (95% CI, 65% – 85%) at 12 months and 66% (95% CI, 58% – 79%) at 24 months. The safety profile observed in this updated analysis was consistent with previously reported results, with no emergence of new safety signals. Grade 3/4 cytokine release syndrome (CRS) – as defined by the rigorous Penn Grading Scale – occurred in 49% of patients. Within eight weeks of infusion, 13% of patients experienced grade 3 neurological events, with no grade 4 events or cerebral oedema2. These updated data will be presented in an oral session at the ASH (Free ASH Whitepaper) annual meeting (Abstract # 895; Monday, December 3, 4:30PM PST).

Results from the 19-month analysis from the JULIET study of Kymriah in adult patients with r/r DLBCL (n=99) indicated prolonged durability of response in patients who had previously been through multiple rounds of chemotherapy and unsuccessful stem cell transplants (Abstract # 1684). The overall response rate (ORR) after a median of 19 months of follow-up was 54% (95% CI, 43% – 64%; CR, 40%; partial response [PR], 13%) among patients who were followed for at least 3 months or discontinued earlier. The mDOR was not reached at the time of analysis indicating most responders were still experiencing a response at the time of analysis; and the relapse-free probability, which was 66% (95% CI, 51%-78%) at 6 months, remained consistent at 64% (95% CI, 48%-76%) between 12-month and 18-month analyses. Further, 54% (15/28) of patients who had achieved a PR converted to CR. Median OS for all infused patients was 11.1 months (95% CI, 6.6 months-NE) and not reached (95% CI, 21 months-NE) for patients in CR. The OS probability was 48% (95% CI, 38%-57%) at 12 months and 43% (95%CI, 33%-53%) at 18 months (max follow-up, 29 months). Analyses of ORR, DOR and OS data showed consistent results across all patient subgroups, regardless of relapsed/refractory status, age and high-risk cytogenetics.

The safety profile observed in the 19-month follow-up from JULIET continued to be consistent with previous reports and no deaths occurred due to causes other than disease progression in this longer-term follow up analysis. Within eight weeks of infusion with Kymriah, Grade 3/4 CRS, as defined by the Penn Grading Scale, was reported in 23% of patients. CRS management was conducted per the Penn CRS management algorithm, which is specific to Kymriah. Tocilizumab and steroids were used in 16% and 11% of patients, respectively, to treat CRS. Eleven percent of patients had Grade 3/4 neurologic adverse events, which were managed with supportive care3.

Oxford BioMedica is the sole manufacturer of the lentiviral vector used in Kymriah. The Group signed an agreement with Novartis in July 2017 for the commercial and clinical supply of lentiviral vectors used to generate Kymriah and other undisclosed CAR-T products. This collaboration has reached important milestones in 2018 with the US FDA approval of Kymriah to treat adult patients with r/r DLBCL, and the approval of Kymriah in these two distinct indications in the European Union, Canada and Switzerland. These important achievements follow the initial US launch of Kymriah in paediatric and young adult patients with r/r B-cell ALL in 2017. Oxford BioMedica signed an agreement with Novartis in July 2017 for the commercial and clinical supply of lentiviral vectors used to generate CTL019 and other undisclosed CAR-T products, for which Oxford BioMedica could potentially receive in excess of $100m from Novartis over the next three years.

Notes for editors

About the ELIANA Trial

ELIANA is the first paediatric global CAR-T cell therapy registration trial, examining patients in 25 centres in 11 countries across the US, Canada, Australia, Japan and the EU, including: Austria, Belgium, France, Germany, Italy, Norway and Spain, demonstrating effective distribution of Kymriah across four continents using a global supply chain. In 2012, Novartis and Penn entered into a global collaboration to further research, develop and commercialize CAR-T cell therapies, including Kymriah, for the investigational treatment of cancers.

About the JULIET Trial

JULIET is the first multi-centre global registration study for Kymriah in adult patients with r/r DLBCL. JULIET, led by researchers at the University of Pennsylvania, is the largest and only global registration study examining a CAR-T cell therapy in DLBCL, enrolling patients from 27 sites in 10 countries across the US, Canada, Australia, Japan and Europe, including Austria, France, Germany, Italy, Norway and the Netherlands.

About Kymriah

In August 2017, Kymriah became the first available chimeric antigen receptor T cell (CAR-T) therapy when it received FDA approval for children and young adults with B-cell acute lymphoblastic leukaemia (ALL) that is refractory or has relapsed at least twice. Kymriah is a novel immunocellular therapy and a one-time treatment that uses a patient’s own T cells to fight cancer. Kymriah uses the 4-1BB costimulatory domain in its chimeric antigen receptor to enhance cellular expansion and persistence.

On December 1, 2018 X4 Pharmaceuticals, a clinical stage biotechnology company developing novel CXCR4 allosteric antagonist drugs to improve immune cell trafficking to treat rare diseases and cancer, reported the presentation of additional Phase 2 clinical data demonstrating a positive safety profile and clinical activity of X4P-001 in patients with WHIM syndrome, a rare primary immunodeficiency disease (Press release, X4 Pharmaceuticals, DEC 1, 2018, View Source [SID1234531788]). The clinical results are being presented today in a poster session at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting taking place in San Diego.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We continue to see encouraging results from this Phase 2 trial, as X4P-001 drug exposure appears to correlate with increases in absolute neutrophil count and absolute lymphocyte count levels. Increases in these biomarkers are an indication of potential improvement in the pathophysiology underlying WHIM syndrome. An example of clinical improvement and impact on symptoms was the continued reduction in a WHIM patient’s human papillomavirus-related warts following X4P-001 therapy," said David C. Dale, MD, Professor of Medicine at the University of Washington School of Medicine, Seattle, WA, and lead investigator of the trial.

The poster presentation at ASH (Free ASH Whitepaper) describes results from the first 8 patients with genetically confirmed WHIM syndrome and demonstrates the dose-dependent biomarker activity used to support dose selection for the Phase 3 trial. Additional updates on safety and clinical activity across all patients who were enrolled as of the August 17, 2018 data-cut off are also presented in the poster.

Information about the clinical trial of X4P-001 in patients with WHIM syndrome can be found on clinicaltrials.gov: View Source

"X4P-001 in WHIM syndrome is X4’s lead product candidate and our team is rapidly advancing toward the Phase 3 trial, with the goal of delivering X4P-001 to the global community of WHIM patients who currently lack any approved treatment specifically for this disease," said Paula Ragan, PhD, president and chief executive officer of X4 Pharmaceuticals. "We are confident in our path forward based on these favorable Phase 2 results, and we look forward to starting the pivotal Phase 3 trial in the first half of 2019."

About WHIM Syndrome
WHIM syndrome is a primary immunodeficiency disease caused by genetic mutations in the CXCR4 receptor gene resulting in susceptibility to certain types of infections. WHIM is an abbreviation for the characteristic clinical symptoms of the syndrome: Warts, Hypogammaglobulinemia, Infections, and Myelokathexis. Within the overall category of primary immunodeficiencies, there are between 15,000 and 100,000 patients in the U.S. who are classified with primary immunodeficiency disease of unknown origin – of which WHIM is one.1,2,3 WHIM syndrome is a rare disorder and the precise prevalence or incidence of patients that have the genetic mutation responsible for WHIM syndrome is unknown. Individuals with WHIM syndrome are more susceptible to potentially life-threatening bacterial infections.4 Additionally, WHIM syndrome is associated with significant morbidity beginning in early childhood and continuing throughout life. Current therapy is limited to treatment of acute infections with antibiotics or prevention of infections through the use of intravenous immunoglobulin or G-CSF. There is no approved therapy for the treatment of WHIM syndrome.

On December 1, 2018 ArQule, Inc. (Nasdaq:ARQL) reported that it will present clinical data on the company’s BTK inhibitor, ARQ 531, in a poster presentation at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition to be held from December 1 to 4, 2018 in San Diego (Press release, ArQule, DEC 1, 2018, View Source [SID1234531787]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Updated safety, PK, biomarker and anti-tumor activity data from the company’s Phase 1 dose escalation study in patients with relapsed or refractory hematologic malignancies (ARQ 531-101) will be presented.

Presentation Details

Title:

A Phase 1 Dose Escalation Study of ARQ 531 in Selected Patients with Relapsed or Refractory Hematologic Malignancies

Abstract #: 3136
Session: CLL: Therapy, excluding Transplantation: Poster II
Date: Sunday, December 2, 2018
Time: 6:00-8:00 p.m. PT
Location: San Diego Convention Center, Hall GH

About BTK and ARQ 531
Bruton’s tyrosine kinase, BTK, is a therapeutic target that has been clinically proven to inhibit B-cell receptor signaling in blood cancers. ARQ 531 is an orally bioavailable, potent and reversible BTK inhibitor. Biochemical and cellular studies have shown that ARQ 531 inhibits both the wild type and C481S-mutant forms of BTK. The C481S-mutation is a known resistance mechanism for first generation irreversible BTK inhibitors. In preclinical studies, ARQ 531 has demonstrated good oral bioavailability as well as favorable pharmacokinetic, pharmacodynamic and metabolic properties.

On December 1, 2018 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly-targeted and immuno-oncology drugs for the treatment of cancer, reported the presentation of clinical data from two ongoing trials of its investigational Bruton’s tyrosine kinase (BTK) inhibitor, zanubrutinib, in patients with mantle cell lymphoma (MCL) (Press release, BeiGene, DEC 1, 2018, View Source;p=irol-newsArticle&ID=2378923 [SID1234531783]). The presentations were made at the 60th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper), taking place December 1-4, 2018 in San Diego, CA.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Results from the pivotal Phase 2 trial of zanubrutinib in Chinese patients with relapsed or refractory (R/R) MCL (ClinicalTrials.gov Identifier: NCT03206970) were featured in an oral presentation, while updated results from the global Phase 1 trial of zanubrutinib in patients with multiple subtypes of B-cell malignancies, including treatment naïve (TN) and R/R MCL (ClinicalTrials.gov Identifier: NCT02343120), were featured in a poster presentation.

"Taken together, we believe that these two studies provide encouraging evidence for the use of zanubrutinib as a potential therapy in patients with MCL," said Jane Huang, M.D., Chief Medical Officer, Hematology, at BeiGene. "The results from 86 patients enrolled in our pivotal Phase 2 study in Chinese patients with R/R MCL presented today at ASH (Free ASH Whitepaper), provide a thorough look into the data included in our first new drug application (NDA) in China for zanubrutinib. Additionally, the results from 48 patients with MCL enrolled in our global Phase 1 study illustrated consistent outcomes for patients studied outside of China. We are excited by the prospect that zanubrutinib may be a differentiated BTK inhibitor with deep, durable responses for patients with MCL and potentially for other B-cell malignancies."

Zanubrutinib was discovered by BeiGene scientists, and is being developed globally as a monotherapy and in combination with other therapies to treat various hematologic malignancies. Zanubrutinib is being studied in several clinical trials as part of a broad development program and was granted Fast Track Designation by the U.S. Food and Drug Administration (FDA) for the treatment of patients with Waldenström macroglobulinemia (WM). BeiGene plans to submit an initial NDA to the FDA for zanubrutinib in 2019 or early 2020. The NDAs in China for R/R MCL and R/R chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) have been accepted by the National Medical Products Administration (NMPA, formerly known as CFDA) and the MCL filing has been granted priority review.

"Zanubrutinib was shown to be highly active in Chinese patients with R/R MCL, as evidenced by a high rate of complete responses characterized by PET-based imaging. It was also generally well-tolerated, and we are hopeful of its potential to become a new treatment option for Chinese patients with MCL and potentially other forms of B-cell lymphomas," said Yuqin Song, M.D., Ph.D., Associate Professor of Medical Oncology, Deputy Director of the Lymphoma Department at Peking University Cancer Hospital in China, and presenter of results from the pivotal Phase 2 trial in Chinese patients.

"The outcomes observed in patients treated outside of China are generally consistent with the experiences observed in Chinese patients with R/R MCL. Importantly, the high response rates that were observed appear to extend to patients with both TN and R/R MCL," commented Constantine Tam, M.D., Disease Group Lead for Low Grade Lymphoma and Chronic Lymphocytic Leukemia at Peter MacCallum Cancer Center and Director of Hematology at St. Vincent’s Hospital, Australia, and lead author of the poster presentation of results from the global Phase 1 trial.

Summary of Clinical Results From the Pivotal Phase 2 Trial in China
Oral Presentation Data Included in BeiGene’s NDA in China for Zanubrutinib in MCL

This single arm, open-label, multi-center, pivotal Phase 2 trial of zanubrutinib as a monotherapy in Chinese patients with R/R MCL enrolled 86 patients who had received a median of two prior lines of therapy (1-4). Patients were treated with zanubrutinib, dosed at 160 mg orally twice-daily (BID). The primary endpoint of the trial was overall response rate (ORR) assessed by independent review committee (IRC) using PET-based imaging according to the Lugano Classification 2014.

As of March 27, 2018, 85 patients with R/R MCL were evaluable for efficacy and 65 patients (75.6%) remained on study treatment. The median follow-up time for patients enrolled in the trial was 35.9 weeks (1.1-55.9). Results included:

The ORR by IRC was 83.5 percent (71/85); the complete response (CR) rate was 58.8 percent (50/85) and the partial response (PR) rate was 24.7 percent (21/85);

The 24-week progression-free survival (PFS) was estimated at 82 percent. The median PFS had not yet been reached;

With 24.1 weeks median follow-up (0.1-41.1), the median duration of response (DOR) had not yet been reached and 90 percent of responders were still in response at 24 weeks;

Zanubrutinib tolerability was generally consistent with previous reports in patients with various B-cell malignancies and the majority of adverse events (AEs) were grade 1 or 2 in severity. The most frequent AEs of any attribution were neutrophil count decreased (31.4%), rash (29.1%), upper respiratory tract infection (29.1%), and platelet count decreased (22.1%);

The most frequently reported (in >5 percent of patients) grade 3 or higher AEs were neutrophil count decreased (11.6%) and lung infection (5.8%);

Four patients (4.7%) had treatment emergent adverse events (TEAEs) leading to death (one case each of traffic accident, cerebral hemorrhage, pneumonia, and unknown cause in the setting of infection); and

Among events of special interest for BTK inhibitors, diarrhea was observed in nine patients (10.5%), all grade 1-2. Major hemorrhage was observed in 1 patient (1.2%) with blastoid variant of MCL who had intra-parenchymal CNS bleeding. No cases of atrial fibrillation/flutter were reported in this trial.
Summary of Updated Clinical Results From the Global Phase 1 Trial

This open-label Phase 1 trial of zanubrutinib as a monotherapy in patients with different subtypes of B-cell malignancies, including MCL, is being conducted in Australia, New Zealand, the United States, Italy, and South Korea. As of July 24, 2018, 48 patients with TN (n=9) or R/R (n=39) MCL have been enrolled in the trial and the median follow-up time was 12.7 months (0.7-38.0). Forty-five patients including six with TN and 39 with R/R MCL, were evaluable for efficacy in this analysis, per the Lugano 2014 classification. At the time of the data cutoff, 26 patients remained on study treatment. Updated results included:

The ORR by investigator was 88.9 percent (40/45); the CR rate was 26.7 percent (12/45) and the PR rate was 62.2 percent (28/45). The majority of patients were assessed via CT-scan; PET scans were optional per trial protocol;

The median DOR was 16.2 months and the median PFS for R/R patients was 18.0 months (0.7-30.7);

Zanubrutinib tolerability was generally consistent with previous reports in patients with various B-cell malignancies and the majority of AEs were grade 1 or 2 in severity. The most frequent AEs of any attribution were petechia/purpura/contusion (33.3%), diarrhea (33.3%), upper respiratory tract infection (29.2%), fatigue (25.0%), and constipation (18.8%);

Grade 3-5 AEs occurred in 56.3 percent of patients. Grade 3-5 AEs of any attribution reported in > three patients included anemia (8.3%), major hemorrhage (6.3%), cellulitis (6.3%), myalgia (6.3%), neutropenia (6.3%), pneumonia (6.3%); and thrombocytopenia (6.3%);

Discontinuation due to AEs occurred in 18.8 percent of patients with all but one event (peripheral edema) determined to be unrelated to study drug; and

There were four deaths due to AEs, which were all determined by the investigators to be unrelated to zanubrutinib treatment.
Investor Webcast

Date and Time: Monday, December 3, 2018 at 20:00 PST (Tuesday, December 4 at 12:00 China Standard Time)
Webcast: A live webcast and replay of the event will be available on BeiGene’s investor website, View Source
About Mantle Cell Lymphoma
Lymphoma is a diverse group of malignancies that originates from B-, T- or NK- cells. Mantle cell lymphoma (MCL) is typically an aggressive form of non-Hodgkin lymphoma (NHL) that arises from B-cells originating in the "mantle zone." In 2013, the incidence of lymphoma was 4.2 per 100,000 and the mortality was 2.2 per 100,000 in mainland Chinai, making it the eleventh most common cancer and the tenth leading cause of cancer death.ii In the United States, about 70,800 new cases of NHL were expected in 2014, with MCL representing about six percent (about 4,200 cases) of all new cases of NHL in the United Statesiii. Mantle cell lymphoma usually has a poor prognosis, with a median survival of three to four years, although occasionally patients may have an indolent course.iv Frequently, mantle cell lymphoma is diagnosed at a later stage of disease.

About Zanubrutinib
Zanubrutinib (BGB-3111) is an investigational small molecule inhibitor of Bruton’s tyrosine kinase (BTK) that is currently being evaluated in a broad pivotal clinical program globally as a monotherapy and in combination with other therapies to treat various B-cell malignancies.

Clinical trials of zanubrutinib include a global Phase 1 trial; a fully-enrolled, global Phase 3 clinical trial in patients with Waldenström macroglobulinemia (WM) comparing zanubrutinib to ibrutinib, the currently approved BTK inhibitor for WM; a global Phase 3 clinical trial in patients with previously untreated chronic lymphocytic leukemia (CLL); a pivotal Phase 2 trial in patients with relapsed/refractory (R/R) follicular lymphoma in combination with GAZYVA (obinutuzumab); and a Phase 3 trial comparing zanubrutinib to ibrutinib in patients with R/R CLL/small lymphocytic lymphoma (SLL). In China, BeiGene has completed enrollment in two other pivotal Phase 2 clinical trials of zanubrutinib in patients with CLL/SLL and WM. New drug applications (NDA) for zanubrutinib in patients with R/R MCL and in patients with R/R CLL/SLL have been accepted by the National Medical Products Administration (NMPA, formerly known as CFDA) and the MCL filing has been granted priority review.